Cancer remains a most life-threatening disease worldwide. Conventional radiotherapy and chemotherapy are generally regarded palliative only to slow down tumor growth and prolong patient survival, yet at a cost of systemic adverse effects. The best curative option is radical surgery, but only a limited number of patients are suitable due to unfavorable location, staging and extent of the tumor. Furthermore, limited functional reserve of the organ after partial resection is also associated with a higher post-operative risk. Societal communities, healthcare institutions and medical professionals have put tremendous efforts in the research and development of new treatments to combat cancer. Among newly developed anticancer therapies, vascular targeting agents (VTAs) selectively disrupt the cytoskeleton of endothelial cells of neovasculature and cause shutdown of tumoral blood supply and subsequent tumor cell starvation and death [Thorpe P E. Clin Cancer Res. 2004; 10: 415-27]; radiofrequency ablation (RFA) is a minimally invasive procedure that utilizes heat converted from RF energy to destroy biological tissues particularly for the treatment of solitary tumors [Ni Y, et al; Abdominal Imaging 2005; 30: 381-400]; photodynamic therapy (PDT) combines administration of a drug or photosensitizer with light illumination of certain wavelength to kill cancer cells by the generated cytotoxic species [Pass H, JNatl Cancer Inst 1993; 85: 443-56]. A common noticeable consequence of these therapies is creation of tumor necrosis. On the other hand, the use of pyruvate dehydrogenase kinase inhibitors such AZD7545, dichloroacetate (DCA), sodium dichloroacetate, trichloroacetate, difluoroacetate, 2-chloropropionate, 2,2′-dichloropropionate, chloropropionate, halogenated acetophenones inhibitors, radicicol oxime or radicicol that that blocks mitochondrial pyruvate dehydrogenase kinase (PDK) shifting metabolism from glycolysis to glucose oxidation promoting apoptosis in cancer tumors [Alla Klyuyeva et al. FEBS Lett. 2007 June 26; 581(16): 2988-2992 and Biochem. J. 329 191. Bonnet et al (2007)*.
Despite encouraging preclinical and clinical outcomes with RFA, VTAs and PDT as well as other conventional nonsurgical anticancer treatments to induce therapeutic tumor necrosis, marginal or sporadic tumor residues are frequently attributed to the eventual incomplete treatment and tumor relapse [Ni Y, Miao Y, et al. Eur Radiol 2000; 10: 852-4 and Thoeny H C, et al. Radiology 2005; 237:492-9.].
Present invention demonstrates that small therapeutically labeled necrosis-avid compounds (SRaLNACs, MW<1-2 K Dalton) such as the therapeutically labeled napthodianthrone or phenanthro[1,10,9,8-opqra]perylene-7,14-dione compound with a high in vivo target-to-nontarget ratio of, for instance, 10-100 (in contrast to other compounds with a poor target-to-nontarget ratio of, for instance, close to 1.0) can be applied in combination with any necrosis-inducing anticancer therapies to prevent the formation of rims or clusters of viable tumor cells, and thus synergistically augment tumoricidal efficacy and cancer curability.
The therapeutically labeled napthodianthrone or phenanthro[1,10,9,8-opqra]perylene-7,14-dione compound can be used to block the proliferation reaction of viable tumor cells as a response to tumor damage, tumor ablation or tumor destruction, to block tumor cell proliferation as response to an incomplete antitumor treatment, to prevent repopulation of tumor cells in solid tumors after physically or chemically induced tumor destruction, to prevent re-growth of tumors after chemotherapy induced tumor shrinkage, or to remove the remaining antitumor-drug resistance cancer cells in the primary or metastatic solid tumors or in the locoregional tissues adjacent to such tumors. Suitable therapeutic labels for napthodianthrone or phenanthro[1,10,9,8-opqra]perylene-7,14-dione compound to obtain such radio-emitters are from the group consisting of 153Samarium, 156Holmium, 165Dysprosium, 203Lead, 186Rhenium, 88Rhenium, 211Bismuth 212Bismuth, 213Bismuth, and 214Bismuth, 153Sm, 159Gd, 186Re, 166Ho, 90Yttrium, 91Yttrium, 88Yttrium, 89Yttrium and 131Iodine.